Rapidly disintegrating methylcellulose tablets

ABSTRACT

The present invention relates to a process for preparing a tablet formation. The process has the steps of granulating a methylcellulose, granulating a diluent, and blending the granulated methylcellulose and the granulated diluent to form an intragranulated tablet formation.

FIELD OF THE INVENTION

The present invention relates to an improved process for preparingcompressed methylcellulose containing tablets which meet USPdisintegration standards.

BACKGROUND OF THE INVENTION

The history of cellulose ethers, such as methylcellulose andcarboxymethylcellulose suggests that these agents are effective as bulklaxatives. Their mechanism of action involves increasing both the watercontent of, and the bulk content of the stool, as well as lubricatingthe stool; thereby relieving constipation.

Cellulose ethers have been administered as bulk laxatives in dosageforms comprising of tablets, suspensions, and bulk powders; the latteras sugar-free or in compositions containing high amounts of sugar.

Cellulose ethers administered as suspensions in water may contain highconcentrations of sucrose or other sugars and flavors. In suchformulations, the sugar competes with the cellulose ether for availablewater, thereby preventing the cellulose ether from hydratingsufficiently to form a gel. The advantages of using a suspensionformulation is that the cellulose ether is dispersed sufficiently toavoid any significant lumping in the digestive tract. However, thesesuspensions are viscous, semi-gelatinous, and visually unappealing tothe consumer. Another disadvantage is the unpalatability of thesuspensions due to the slimy mouth feel and extreme sweetness of suchsuspensions. Hence, these dosage forms have not gained significantconsumer acceptance.

Bulk powders of cellulose ethers often exhibit lumping of individualparticles and gelation and thus, remain undissolved as they pass throughthe digestive tract. Additionally, administration of bulk powders hascaused cramping, nausea, and vomiting in some patients. Therefore, bulkpowders are not the preferred dosage form for cellulose ethers.

Palatable and visually appealing bulk powders have, however, beenaccomplished by addition of water or another aqueous liquid to a drypowder mix of a water-soluble cellulose ether and a dispersingagent/sweetening component, typically sugar. This technology isdisclosed in South African patent No. 84,1044, published Sep. 26, 1984.The pitfall with these compositions is that they contain about 400calories of nutritive value per dose, primarily due to the high sugarcontent. This high caloric value is not acceptable to the averageconsumers or to users suffering from blood sugar disorders, includingdiabetics. Elderly people are normally, the common strata of thepopulation that suffers from constipation and the more frequent users oflaxatives, and are also commonly suffering with blood sugar disorders.The consumption of large quantities of sugar could aggravate blood sugardisorders.

Sugar encrusted cellulose ethers have been proposed as alternatives tothe bulk powders containing high amounts of sugar. Such formulationshave 1) less sugar such as natural sugar or combination of sugars suchas sucrose, glucose, fructose or corn syrup solids; 2) lower caloricvalue; and 3) are readily dispersed in cold aqueous liquids.

Citrucel® Orange Flavor, a bulk forming laxative containingmethylcellulose as its active ingredient, was first introduced into themarket in 1986. This product contains 15 g of sucrose in a 19 g adultdose, which corresponds to a 2 g dose of methylcellulose. To decreasethe sugar content of this product, a natural flavored formula lower incaloric value, and containing only 1 g sucrose, was developed andintroduced in 1988. Additional patent protection for this product hasfocused on producing a sugar-free and virtually calorie-free powder. Theproduct has a sugar-free sweetener, a dispersing agent, otherexcipients, and flavoring and was marketed in 1991 as Sugar FreeCitrucel® Orange Flavor.

There still remains a need in the art to develop a rapidlydisintegrating solid dosage form of a bulk agent, preferablymethylcellulose, which is convenient to take and transport, sugar free,and easily administered to the consumer having blood sugar disorders ordiabetics, for instance.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for preparingmethylcellulose tablets which are readily dispersible and meet UnitedStates Pharmacopoeia standards for disintegration. The methylcelluloseis compressed into tablets which contain an edible calcium salt, inpreferred w/w ratios. Preferably the tablets rapidly disintegrate,in-vitro in 0.1N hydrochloric acid and water at 37′ 0.5° C.

DETAILED DESCRIPTION OF THE INVENTION

There is a common belief that tabletted cellulose ethers do not readilydissolve in the digestive tract because these cellulose ethers arehighly hygroscopic. The outer portion of the tablet is said to form agel-like hydrate that prevents the tablet from breaking up and greatlyretards the hydration of the inner portion of the tablet. The presentinvention overcomes this art recognized problem and involves preparationof a novel composition, and process of making, by which a rapidlydisintegrating tablet of methylcellulose is prepared.

The tablets are prepared by a novel process involving a high-shear wetgranulation method, followed by fluidized bed drying, milling, mixingwith the other ingredients, and compression.

The present invention is to a methylcellulose tablet which comprisesmethylcellulose having a viscosity of >1000 centipoise, and at least oneexcipient selected from an edible calcium salt. It is recognized thatthe formulation will also include diluents and fillers well known to theskilled artisan.

The tablet formulations of the present invention are advantageous overother dosage forms of methylcellulose because of their convenience ofadministration and rapid disintegration. This is in contrast to tabletsof methylcellulose, formulated as 100% w/w methylcellulose in a 0.5 gmcaplet which have been found not to disintegrate in 0.1N HCl solution,using a conventional dissolution apparatus even after two hours. Thepresent tablets should disintegrate in 0.1N HCl from about 20 to about30 minutes, preferably from about 10 to about 19 minutes, and morepreferably less than 10 minutes; and in water, the tablets shoulddisintegrate from about 25 to about 30 minutes, preferably from about 15to about 24 minutes, and more preferably less than 15 minutes.

It has been found that low molecular weight (mw) methylcellulose is lesseffective for use as a laxative, and therefore is less desirable for usein a rapidly disintegrating tablet formulation. Higher molecular weightmethylcellulose is therefore both desirable and necessary in the presentinvention. The fibers must have a sufficient viscosity to gel and retainwater in the gut to provide the stool bulking and softening for laxationuse.

By using the testing methods for methylcellulose under standardconditions, such as those found in the USP XXII, p. 894, ApparentViscosity method for Methylcellulose, or as discussed in Handbook ofPharmaceutical Excipients, APhA, a preferred methylcellulose for useherein should have a viscosity of >1000 centipoises (cps),preferably >2000 centipoises, more preferably >3000 centipoises, andmost preferably >4000 centipoise. Higher molecular weightmethylcellulose than those described is also desirable, however, thecommercially availability of this grade of methylcellulose being thelimiting feature. At present the upper limit commercially available isabout 6000 cps, which is encompassed within the scope of this invention.One presently available methylcellulose product for use herein isMethocel A4M, made by Dow Chemical Company, Midland Mich. as DowMethocel A4M, having a viscosity of about 3000 to about 5,600 cps, whichis within 75 to 140% of the desired target viscosity herein.

Some of the additional diluents or fillers for use in this formulationare preferably swellable agents, and may include, but are not limitedto, various grades of microcrystalline cellulose, such as Avicel PH101,Avicel PH102, & Avicel PH200; Corn starch; or Starch 1500.

The edible calcium salts suitable for use herein include but are notlimited to, dibasic calcium phosphate dihydrate, calcium phosphateanhydrous, and tribasic calcium phosphate; or mixtures thereof. Apreferred edible calcium salt is the dibasic calcium phosphate dihydratesalt, which salt also provides good compressibility.

If microcrystalline cellulose is added, it is preferably from about 50to 180 microns in size, more preferably about 50. Avicel PH 101 has amean particle size of about 50; Avicel PH 102 has a mean particle sizeof about 100; and Avicel PH 200 has a mean particle size of about 190microns. Preferably the preferred microcrystalline cellulose is AvicelPH 101.

It is noted that the ratio of methylcellulose to edible calcium salt,and additional diluents will depend upon the diluent chosen, and iswithin the skill of the art to determine with preciseness the necessaryratios.

Suitable ratios for particular diluents however, are described below:

-   For Methylcellulose:Dibasic calcium phosphate, dihydrate, from about    2 to about 4:1, preferably from about 2.6-3.1:1;-   For Methylcellulose:Calcium phosphate, anhydrous from about 2 to    about 4:1, preferably from about 3.1:1-   Methylcellulose:Tribasic calcium phosphate, WG® from about 2 to    about 4:1, preferably from about 3.1:1-   For Methylcellulose: microcrystalline cellulose, from about 2:1 to    about 14:1. Preferably for Avicel PH 101 from about 2.2-13.5:1; for    Avicel PH 102 from about 2.4-8.3:1; and for Avicel PH 200 from about    2.4-4:1.-   For Methylcellulose:Corn starch from about 7.5 to about 15,    preferably from about 13.5:1;-   For Methylcellulose:Starch 1500, from about 2.0 to about 5.0:1,    preferably from about 2.4:1;-   For Methylcellulose:Explotab, from about 5 to about 25:1, preferably    from about 8.1 to about 21.3:1.

It is recognized that with the edible calcium salt, the formulation mustalso have an ingredient which keeps the granules together, i.e. abinding agent. A preferred binding agent is PVP, or the alternativeagents noted below.

In addition to the above noted edible calcium salt(s), optional diluentsor fillers, and binding agent(s), the formulation may also includeadditional components such as, but are not limited to, a wetting agent,(super)disintegrant(s), a second binding agent(s), dye(s) or colouringagents, and lubricants, which are preferably used to prepare a tabletthat is wetted readily, and is rapidly disintegrated in 0.1Nhydrochloric acid and water, the USP test standard test formethylcellulose.

A preferred wetting agent is sodium lauryl sulfate.

A preferred lubricant is magnesium stearate.

A preferred binding agent is polyvinylpyrrolidone, or PVP, such asPovidone 29K/32. Preferably, the PVP is present in an amount of about 4to about 6.5% w/w.

A preferred disintegrating agent is sodium starch glycolate, such asExplotab®. Preferably, the sodium starch glycolate is present in anamount of about 3 to about 8% w/w.

As various excipents and diluents will be formulated together, and usedin combination herein, suggested % w/w ratios for various formulationsare presented below. While not all of these ratios include the ediblecalcium salts, these are merely illustrative of the invention and theskilled artisan will readily recognize how to formulate the product ofthis invention with the addition of the edible calcium salts.

-   Sodium lauryl sulfate:Explotab:Dibasic calcium phosphate,    dihydrate:Povidone 29K/32:Magnesium stearate include:    0.38-0.40:3.5-7.9:20.6-24.8:4.0-6.5:0.5-1.0-   Sodium lauryl sulfate:Explotab:Tribasic calcium phosphate WG®:    Povidone 29K/32:Magnesium stearate include: 0.40:3.5:21.6:6.4:1.0-   Sodium lauryl sulfate:Explotab:Calcium phosphate, anhydrous:    Povidone 29K/32:Magnesium stearate include: 0.40:3.5:21.6:6.4:1.0-   Methylcellulose:sodium lauryl sulfate (SLS), from about 60 to about    170:1, preferably from about 155:1-170:1;-   Methylcellulose:Povidone, preferably PVP 29K/32, from about 8 to    about 22:1, preferably from about 10.4:1-16.7:1;-   Methylcellulose:Magnesium stearate from about 50 to about 150;1,    preferably from about 58-132:1;-   Sodium lauryl sulfate:Explotab:Avicel PH 101®: Povidone    29K/32:Magnesium stearate include:    0.35-0.46:3.05-6.17:4.38-27.13:4.38-6.66:0.76-1.14-   Sodium lauryl sulfate:Explotab:Avicel PH 102®: Povidone    29K/32:Magnesium stearate include:    0.35-0.46:4.9-6.17:9.21-25.53:4.38-6.66:0.76-1.14-   Sodium lauryl sulfate:Avicel PH 200®: Povidone 29K/32:Magnesium    stearate include: 0.38-0.42:19.27-25.53:5.99-6.66:0.94-1.04-   Sodium lauryl sulfate:Explotab:Com starch: Povidone 29K/32:Magnesium    stearate include: 0.36-0.38:3.66-7.07:4.35-4.68:4.35-4.68:0.88-0.95-   Sodium lauryl sulfate:Explotab:Starch 1500®: Povidone    29K/32:Magnesium stearate include:    0.36-0.38:3.66-7.07:24.05-25.89:4.35-4.68:0.88-0.95

Not wishing to be limited to the explicit excipients noted above, thefollowing alternative agents may also be used herein.

Alternatives lubricants to magnesium stearate include, but are notlimited to, calcium stearate, sodium stearate, Cab-O-Sil, Syloid,stearic acid and talc.

Alternatives binding agents to PVP include but are not limited to,hydroxypropylcellulose, hydroxypropyl methylcellulose, acacia, gelatin,tragacanth, pregelatinized starch and starch.

Alternatives disintegrants to Explotab® include but are not limited to,sodium carboxymethylcellulose, Ac-di-sol®, carboxymethylcellulose,veegum, alginates, agar, guar, tragacanth, locust bean, karaya, pectin,and crospovidone.

Alternative wetting agents to sodium lauryl sulfate, include but are notlimited to, magnesium lauryl sulfate.

All of these formulations can be prepared with and without sugar. Asugar-free formulation has the advantage that it can be administeredeasily to consumers with blood sugar disorders or to diabetics in needof such preparations.

Another advantageous property of the present invention is that theformulations contain calcium, such as dibasic calcium phosphatedihydrate. These formulations, for instance, will contain approximatelyan 80 mg/dose, anticipating formulating a 0.5 gm/tablet ×2 tablets/doseof methylcellulose. If desired the amount of calcium can be increased inthese tablets to provide increased therapeutic value to the consumer.

The amount of methylcellulose present in each dose, as well as thenumber of doses of laxative taken per day, will depend somewhat on theage, sex, size of the patient, severity of the patient's particularproblem, the advice of the treating physician, if any, and theparticular taste and habits of the patient. Accordingly, the tablets ofthis invention are advantageously administered in a single dose whichmay contain as much as 500 to 1000 mg of methyl cellulose tablet, or ina plurality of smaller doses containing as little as 250 mg per tablet.Most preferably, for laxative effect, each tablet will contain about 500mg methylcellulose and the patient may take 1 to 2 tablets per dose.This dosage, of 1000 mg should adequately provide optimal laxativeefficacy. Therefore, a preferred range of methylcellulose per tablet isoptimally from about 450 to 550 mg, preferably about 500 mg; oralternatively from about 200 to about 300 mg for a smaller tablet,preferably about 250 mg; or even in increments of about 125 mg tablet,i.e. 75 to 175 mg per tablet.

While preferably the compressed tablets are uncoated, they may, ifdesired, be coated with any suitable coating agent well known in theart. Suitably the coating agents are those used for immediate releasepurposes and will dissolve in the gastric juices. Such coating agentsare well known to those skilled in the art and include, but are notlimited to hydroxypropyl methylcellulose, or methyl cellulose, or 20%w/w Opadry II, orange in water.

As will readily be seen by the working examples, there are variouscombinations of intra and extragranular mixing which are possible usingthe ingredients herein. All are encompassed within the scope of thisinvention. Generally, the high viscosity methylcellulose, such asMethocel A4M, will first be granulated with a binder, such as povidone,a wetting agent, such as sodium lauryl sulfate, and a suitable colouringagent to form the intragranular mixture which is then granulated. Thesegranular components are then admixed with additional wetting agents, anddisintegrating agents and finally blended with lubricant. This finalgranular mixture is then blended and compressed into the tablets of thepresent invention.

Therefore, an aspect of the present invention is a process for preparinga tablet formulation which comprises

-   -   a) blending together to form an intragranular mixture high        viscosity methylcellulose of >3000 cps, a wetting agent,        povidone or sodium starch glycolate, and an edible calcium salt;        and    -   b) adding to the mixture of step (a) a PVP aqueous solution, or        alternatively spraying the mixture of step (a) with a PVP        aqueous solution; and preparing granulates; and    -   c) blending together an extragranular mixture of an edible        calcium salt, a wetting agent; a lubricating agent; povidone or        sodium starch glycolate or a mixture thereof; and    -   d) compacting the granulates of step (b) with the extragranular        mixture of step (c).

Another aspect of the present invention is a process for the manufactureof a pharmaceutical tablet, which process comprises mixing

-   -   a) granulates comprising high viscosity methylcellulose of >3000        cps, a wetting agent, povidone or sodium starch glycolate, an        edible calcium salt; and    -   b) blending together an extragranular mixture of an edible        calcium salt, a wetting agent; a lubricating agent; povidone or        sodium starch glycolate or a mixture thereof; and    -   c) compacting the granulates of step (b) with the granular        mixture of step (a); and    -   d) compressing into a tablet.

Another aspect of the present invention is the method of relievingconstipation by increasing the water content of the stool, or byproviding a lubricating effect on the stool in a mammal in need thereof,which method comprises administering to said mammal, an effective amountof a high viscosity methylcellulose compressed into a tablet with asuitable diluent.

Methods of Preparation

The following examples illustrates the invention but is not intended tolimit the scope thereof. All parts and percentages are by weight unlessotherwise indicated. The disintegration time of the formulationsdescribed in the Tables below were obtained by using a conventionaldisintegration apparatus.

EXAMPLE 1

TABLE I Swallowable Methylcellulose Tablets Formula Ingredient g/tablet(% w/w) Phase A Methocel A4M 0.5000 67.27 Dibasic Calcium phosphate,dihydrate 0.0370 4.98 Sodium lauryl sulfate 0.0015 0.20 Dye/Colouringagent 0.0010 0.13 Povidone 29K/32 0.0480 6.46 DI water q.s. q.s. Phase BPhase A 0.5875 79.04 Sodium lauryl sulfate 0.0015 0.20 Sodium starchglycolate 0.0260 3.50 Dibasic Calcium phosphate, dihydrate 0.1245 16.75Magnesium stearate 0.0038 0.51 TOTAL 0.7433 100.00

The process of preparing the rapidly disintegrating tablet ofmethylcellulose is carried out using specified quantities ofingredients, such as those mentioned in TABLE I above, using thefollowing steps:

1. Preparation of Povidone K29/32 (PVP) Solution

The specified amount of PVP was weighed and added to the weighedquantity of water and stirred till all the PVP was dissolved completely.

2. Preparation of Phase A

Accurately weighed amounts of Methocel A4M, calcium phosphate, dibasicdihydrate, sodium lauryl sulfate, and colouring agent, such as anysuitable FD&C Aluminium lake, were transferred to a Key Hi-sheargranulator and mixed for about 10 minutes with impellor speed at 135 rpmand chopper speed at 10%. The PVP solution was sprayed onto the mixturein the granulator at a rate of approx. >200 mL/min. Once addition of PVPsolution was complete, the chopper was stopped. The mixing was continuedin the granulator till resistance reads about 130-135 watts and the timenoted to reach that wattage. A sample was withdrawn from the wetgranulation to record loss on drying (% LOD). The moist granules weredried in the Aeromatic Fluid bed dryer in portions till the % LODreading approximated 1.0-3.0%. The temperature of the air in the fluidbed dryer was maintained at approx. 90-95° C. and the sample was foundto be dry at an outlet air temperature of approx. 32-52° C. The driedgranules were milled through a 12# screen in the Fitz Mill at a highspeed. The granules were weighed and percent yield calculated. Themoisture content was measured for the dry granules. A sample from thegranules was withdrawn and analyzed for particle size distribution, bulkand tap density, flow index, and moisture studies. The granules wereweighed and ingredients of Phase B were calculated based on the weightof remaining granules.

3. Preparation of the Final Blend

To the weighed milled granules produced in Phase A above, specifiedamounts of sodium lauryl sulfate, sodium starch glycolate (Explotab®),and dibasic calcium phosphate, dihydrate were added into the V-blenderand mixed about 10 minutes. Magnesium stearate was then added to theblend and mixed for an additional 3 minutes or so. Samples fromdifferent sections of the V-blender were drawn and submitted foranalyzing blend uniformity. A sample from the final blend was analyzedfor particle size distribution, bulk and tap density, flow index, andmoisture studies. The granules were then weighed.

4. Compression of Methylcellulose Tablets

The final blend was charged into the hopper of a Stokes single punch ‘F’tablet press and compressed into caplets with a suitable tooling. Targethardness desired is between 10 and 25, preferably 8-12 SCU, a preferredtarget weight of each tablet of less than 750 mg; an estimatedfriability of less than 2.0%, more preferably less than 1.0%, and targetdisintegration times below 30 minutes in water and acid (shorterdisintegration times, less than 10 minutes, more preferably less than 8minutes, in 0.1N HCl and less than 15 minutes in water, more preferablyabout 8 minutes, are preferred). The tablets were packaged in Ziplockbags. The tablets were tested for weight variation, hardness,disintegration in acid and water, friability, moisture (% LOD),thickness, viscosity, and content uniformity.

The formulation in TABLE I exhibited a disintegration time of less than5 minutes in 0.1N HCl and less than 9 minutes in water by theconventional USP method using Disintegration Apparatus with disks.

The disintegration time for the formulation of Table 1, Example 1, wasless than 5 minutes in 0.1N HCl was less than 9 minutes in water.

It is noted that Examples 2 to 6, and 11 to 15 are Avicel basedformulations, and Examples 7 to 10 are strach based formulations whichdo not contain an edible calcium salt excipients. These are merely forillustration purposes, and may be formulated to include the ediblecalcium salts as desired using the teachings of this invention andworking examples 1, and 16 to 23.

EXAMPLE 2

A formulation containing both Avicel PH 101® and Explotab®, intra andextragranularly as shown in TABLE II below, exhibited an averagedisintegration time of less than 1 minute in 0.1N HCl at 37±0.5° C.using the automated disintegration apparatus. TABLE II SwallowableMethylcellulose Tablets Formula Ingredient g/tablet (% w/w) Phase AMethocel A4M 0.5000 60.31 Avicel PH 101 ® 0.0370 4.46 Sodium laurylsulfate 0.0015 0.18 Povidone 29K/32 0.0370 4.46 Explotab ® 0.0300 3.62DI water q.s. q.s. Phase B Phase A 0.6055 73.03 Sodium lauryl sulfate0.0017 0.21 Sodium starch glycolate 0.0253 3.05 Avicel PH 101 ® 0.188022.67 Magnesium stearate 0.0086 1.04 TOTAL 0.8291 100.00

EXAMPLE 3

A formulation containing Avicel PHIOI® intragranularly, extragranularAvicel PH 102® and Explotab®, intra and extragranularly, as shown belowin TABLE III exhibited an average disintegration time of less than 3minutes in 0.1N HCl at 37±0.5° C. using the automated disintegrationapparatus. TABLE III Swallowable Methylcellulose Tablets FormulaIngredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 59.24 Avicel PH101 ® 0.0370 4.38 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/320.0370 4.38 Explotab ® 0.0300 3.56 Dye/colouring agent 0.0040 0.47 DIwater q.s. q.s. Phase B Phase A 0.6095 72.21 Sodium lauryl sulfate0.0015 0.18 Sodium starch glycolate 0.0220 2.61 Avicel PH 102 ® 0.203524.11 Magnesium stearate 0.0075 0.89 TOTAL 0.8440 100.00

EXAMPLE 4

A formulation containing Avicel PH101® intragranularly, extragranularAvicel PH 102® and Explotab® intra and extragranularly as shown in TABLEIV below exhibited an average disintegration time of less than 2 minutesin 0.1N HCl at 37±0.5° C. using the automated disintegration apparatus.TABLE IV Swallowable Methylcellulose Tablets Formula Ingredient g/tablet(% w/w) Phase A Methocel A4M 0.5000 59.52 Avicel PH 101 ® 0.0370 4.41Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32 0.0370 4.41 Explotab ®0.0300 3.57 DI water q.s. q.s. Phase B Phase A 0.6055 72.08 Sodiumlauryl sulfate 0.0015 0.18 Sodium starch glycolate 0.0220 2.62 Avicel PH102 ® 0.2035 24.23 Magnesium stearate 0.0075 0.89 TOTAL 0.8400 100.00

In an alternative embodiment of Example 4 a coated version of theformulation shown in TABLE IV was tested for disintegration time. Thecoating solution used was 20% w/w Opadry II, Orange in water. Theaverage disintegration time of coated tablets was less than one minutein 0.1N HCl at 37±0.5° C. using the automated disintegration apparatus.

EXAMPLE 5

A formulation containing Avicel PH101® intragranularly, extragranularAvicel PH 102® and Explotab® intra and extragranularly as shown in TABLEV exhibited an average disintegration time of less than one minute in0.1N HCl at 37±0.5° C. using the automated disintegration apparatus.TABLE V Swallowable Methylcellulose Tablets Formula Ingredient g/tablet(% w/w) Phase A Methocel A4M 0.5000 60.24 Avicel PH 101 ® 0.0370 4.46Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32 0.0370 4.46 Explotab ®0.0300 3.62 DI water q.s. q.s. Phase B Phase A 0.6055 72.95 Sodiumlauryl sulfate 0.0015 0.18 Sodium starch glycolate 0.0110 1.33 Avicel PH102 ® 0.2045 24.64 Magnesium stearate 0.0075 0.90 TOTAL 0.8300 100.00

EXAMPLE 6

A formulation containing Avicel PH 101® intragranularly, extragranularAvicel PH102® and no Explotab® as shown in TABLE VI below, exhibited anaverage disintegration time of less than 3 minutes in 0.1N HCl and lessthan 2 minutes at 37±0.5° C. using the automated disintegrationapparatus. The disintegration times using the conventional apparatuswere about 1 minute in acid and less than 2 minutes in water. TABLE VISwallowable Methylcellulose Tablets Formula Ingredient g/tablet (% w/w)Phase A Methocel A4M 0.5000 67.94 Avicel PH 101 ® 0.0370 5.03 Sodiumlauryl sulfate 0.0015 0.20 Povidone 29K/32 0.0370 5.03 Dye/ColouringAgent 0.0010 0.14 DI water q.s. q.s. Phase B Phase A 0.5765 78.34 Sodiumlauryl sulfate 0.0011 0.15 Avicel PH 102 ® 0.1527 20.75 Magnesiumstearate 0.0056 0.76 TOTAL 0.7359 100.00

EXAMPLE 7

A formulation containing corn starch intragranularly, extragranularStarch 1500 and no Explotab® as shown in TABLE VII exhibited an averagedisintegration time of less than 16 minutes in 0.1N HCl at 37±0.5° C.using the automated disintegration apparatus. TABLE VII SwallowableMethylcellulose Tablets Formula Ingredient g/tablet (% w/w) Phase AMethocel A4M 0.5000 63.29 Corn starch 0.0370 4.68 Sodium lauryl sulfate0.0015 0.19 Povidone 29K/32 0.0370 4.68 Dye/Colouring Agent 0.0010 0.13DI water q.s. q.s. Phase B Phase A 0.5765 72.97 Sodium lauryl sulfate0.0015 0.19 Starch 1500 ® 0.2045 25.89 Magnesium stearate 0.0075 0.95TOTAL 0.7900 100.00

EXAMPLE 8

A formulation containing corn starch intragranularly, extragranularStarch 1500 and intragranular Explotab® as shown in TABLE VIII exhibitedan average disintegration time of less than 14 ninutes in 0.1N HCl at37±0.5° C. using the automated disintegration apparatus. TABLE VIIISwallowable Methylcellulose Tablets Formula Ingredient g/tablet (% w/w)Phase A Methocel A4M 0.5000 61.00 Corn starch 0.0370 4.51 Sodium laurylsulfate 0.0015 0.18 Povidone 29K/32 0.0370 4.51 Explotab ® 0.0300 3.66Dye/Colouring Agent 0.0010 0.12 DI water q.s. q.s. Phase B Phase A0.6065 73.98 Sodium lauryl sulfate 0.0015 0.18 Starch 1500 ® 0.204524.93 Magnesium stearate 0.0075 0.91 TOTAL 0.8200 100.00

EXAMPLE 9

A formulation containing corn starch intragranularly, extragranularStarch 1500 and intra as well as extragranular Explotab® as shown inTABLE IX exhibited an average disintegration time of less than 13minutes in 0.1N HCl at 37±0.5° C. using the automated disintegrationapparatus. TABLE IX Swallowable Methylcellulose Tablets FormulaIngredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 59.88 Cornstarch 0.0370 4.43 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/320.0370 4.43 Explotab ® 0.0300 3.59 Dye/Colouring Agent 0.0010 0.12 DIwater q.s. q.s. Phase B Phase A 0.6065 72.63 Sodium lauryl sulfate0.0015 0.18 Starch 1500 ® 0.2045 24.49 Explotab ® 0.0150 1.80 Magnesiumstearate 0.0075 0.90 TOTAL 0.8350 100.00

EXAMPLE 10

A formulation containing corn starch intragranularly, extragranularStarch 1500 and intra as well as extragranular Explotab® (in higheramounts than shown above in Example 9, TABLE IX) as shown in TABLE Xexhibited an average disintegration time of less than 11 minutes in 0.1NHCl and less than 18 minutes in water at 37±0.5° C. using the automateddisintegration apparatus. TABLE X Swallowable Methylcellulose TabletsFormula Ingredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 58.82Corn starch 0.0370 4.35 Sodium lauryl sulfate 0.0015 0.18 Povidone29K/32 0.0370 4.35 Explotab ® 0.0300 3.53 Dye/Colouring Agent 0.00100.12 DI water q.s. q.s. Phase B Phase A 0.6065 71.35 Sodium laurylsulfate 0.0015 0.18 Starch 1500 ® 0.2045 24.05 Explotab ® 0.0300 3.54Magnesium stearate 0.0075 0.88 TOTAL 0.8500 100.00

EXAMPLE 11

Various formulation containing Avicel PH101® intragranularly anddifferent levels of extragranular Avicel PH102® (as shown in Examples 6,7, and 8 above) were made to observe their effect on disintegration timeof the tablets.

The formulation in TABLE XI, below, exhibited an average disintegrationtime of less than one minute in 0.1N HCl and less than 2 minutes inwater at 37±0.5° C. using the automated disintegration apparatus. Theconventional disintegration apparatus yielded less than 1 minute in bothacid and water. TABLE XI Swallowable Methylcellulose Tablets FormulaIngredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 62.42 Avicel PH101 ® 0.0370 4.62 Sodium lauryl sulfate 0.0015 0.19 Povidone 29K/320.0480 5.99 Dye/Colouring Agent 0.0010 0.12 DI water q.s. q.s. Phase BPhase A 0.5875 73.34 Sodium lauryl sulfate 0.0015 0.19 Avicel PH 102 ®0.2045 25.53 Magnesium stearate 0.0075 0.94 TOTAL 0.8010 100.00

EXAMPLE 12

The formulation in TABLE XII exhibited an average disintegration time ofless than 5 minutes in 0.1N HCl and less than 7 minutes in water at37±0.5° C. using the automated disintegration apparatus. Theconventional disintegration apparatus yielded less than 5 minutes inacid and less than 8 minutes in water. TABLE XII SwallowableMethylcellulose Tablets Formula Ingredient g/tablet (% w/w) Phase AMethocel A4M 0.5000 69.35 Avicel PH 101 ® 0.0370 5.13 Sodium laurylsulfate 0.0015 0.21 Povidone 29K/32 0.0480 6.66 Dye/Colouring Agent0.0010 0.14 DI water q.s. q.s. Phase B Phase A 0.5875 81.48 Sodiumlauryl sulfate 0.0015 0.21 Avicel PH 102 ® 0.1245 17.27 Magnesiumstearate 0.0075 1.04 TOTAL 0.7210 100.00

EXAMPLE 13

The formulation in TABLE XIII exhibited an average disintegration timeof less than 10 minutes in 0.1N HCl and less than 14 minutes in water at37±0.5° C. using the automated disintegration apparatus. Theconventional disintegration apparatus yielded less than 14 minutes inacid and less than 22 minutes in water. TABLE XIII SwallowableMethylcellulose Tablets Formula Ingredient g/tablet (% w/w) Phase AMethocel A4M 0.5000 76.10 Avicel PH 101 ® 0.0370 5.63 Sodium laurylsulfate 0.0015 0.23 Povidone 29K/32 0.0480 7.31 Dye/coloring agent0.0010 0.15 DI water q.s. q.s. Phase B Phase A 0.5875 89.42 Sodiumlauryl sulfate 0.0015 0.23 Avicel PH 102 ® 0.0605 9.21 Magnesiumstearate 0.0075 1.14 TOTAL 0.6570 100.00

EXAMPLE 14

Two formulations containing Avicel PH101® intragranularly with differentevels of extragranular Avicel PH 200® (shown in TABLE XIV and XV below)ere made to observe the effect on disintegration time of tablets.

The formulation in TABLE XIV exhibited an average disintegration time ofless than 7 minutes in 0.1N HCl and less than 9 minutes in water at37±0.5° C. using the automated disintegration apparatus. Theconventional disintegration apparatus yielded less than 8 minutes inacid and less than 13 minutes in water. TABLE XIV SwallowableMethylcellulose Tablets Formula Ingredient g/tablet (% w/w) Phase AMethocel A4M 0.5000 62.42 Avicel PH101 ® 0.0370 4.62 Sodium laurylsulfate 0.0015 0.19 Povidone 29K/32 0.0480 5.99 Dye/Coloring Agent0.0010 0.12 DI water q.s. q.s. Phase B Phase A 0.5875 73.34 Sodiumlauryl sulfate 0.0015 0.19 Avicel PH200 ® 0.2045 25.53 Magnesiumstearate 0.0075 0.94 TOTAL 0.8010 100.00

EXAMPLE 15

The formulation in TABLE XV exhibited an average disintegration time ofless than 4 minutes in 0.1N HCl and less than 7 minutes in water at37±0.5° C. using the automated disintegration apparatus. Theconventional disintegration apparatus yielded less than 5 minutes inacid and less than 9 minutes in water. TABLE XV SwallowableMethylcellulose Tablets Formula Ingredient g/tablet (% w/w) Phase AMethocel A4M 0.5000 69.35 Avicel PH101 ® 0.0370 5.13 Sodium laurylsulfate 0.0015 0.21 Povidone 29K/32 0.0480 6.66 Dye/Coloring Agent0.0010 0.14 DI water q.s. q.s. Phase B Phase A 0.5875 81.48 Sodiumlauryl sulfate 0.0015 0.21 Avicel PH200 ® 0.1245 17.27 Magnesiumstearate 0.0075 1.04 TOTAL 0.7210 100.00

EXAMPLE 16

A formulation containing a calcium source from the intragranular andextragranular excipient, dibasic calcium phosphate, dihydrate withextragranular Explotab® is shown in TABLE XVI.

The formulation in TABLE XVI exhibited an average disintegration time ofless than 6 minutes in 0.1N HCl and less than 9 minutes in water at37±0.5° C. using the automated disintegration apparatus. Theconventional disintegration apparatus yielded less than 5 minutes inacid and less than 12 minutes in water. TABLE XVI SwallowableMethylcellulose Tablets Formula Ingredient g/tablet (% w/w) Phase AMethocel A4M 0.5000 66.93 Dibasic Calcium phosphate, dihydrate 0.03704.95 Sodium lauryl sulfate 0.0015 0.20 F, D, and C Yellow #6 0.0010 0.13Povidone 29K/32 0.0480 6.43 DI water q.s. q.s. Phase B Phase A 0.587578.65 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0.02603.48 Dibasic Calcium phosphate, dihydrate 0.1245 16.67 Magnesiumstearate 0.0075 1.00 TOTAL 0.7470 100.00

EXAMPLE 17

A formulation containing a calcium source from the intra andextragranular excipient, dibasic calcium phosphate, dihydrate with ahigher amount of extragranular Explotab® than in Example 17, is shownbelow in TABLE XVII.

The formulation in TABLE XVII exhibited an average disintegration timeof less than 9 minutes in 0.1N HCl and less than 14 minutes in water at37±0.5° C. using the automated disintegration apparatus. Theconventional disintegration apparatus yielded less than 6 minutes inacid and less than 12 minutes in water. TABLE XVII SwallowableMethylcellulose Tablets Formula Ingredient g/tablet (% w/w) Phase AMethocel A4M 0.5000 65.19 Dibasic Calcium phosphate, dihydrate 0.03704.82 Sodium lauryl sulfate 0.0015 0.20 F, D, and C Yellow #6 0.0010 0.13Povidone 29K/32 0.0480 6.26 DI water q.s. q.s. Phase B Phase A 0.610579.60 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0.02303.00 Dibasic Calcium phosphate, dihydrate 0.1245 16.23 Magnesiumstearate 0.0075 0.97 TOTAL 0.7670 100.00

EXAMPLE 18

Formulations containing a calcium source from the intra andextragranular excipient, dibasic calcium phosphate, dihydrate withdifferent levels of extragranular Explotab®, in combination with similaramount of intragranular Explotab®, are shown below in TABLE XVIII andXIX (Example 19).

The formulation in TABLE XVIII exhibited an average disintegration timeof less than 6 minutes in 0.1N HCl and less than 11 minutes in water at37±0.5° C. using the automated disintegration apparatus. TABLE XVIIISwallowable Methylcellulose Tablets Formula Ingredient g/tablet (% w/w)Phase A Methocel A4M 0.5000 65.19 Dibasic Calcium phosphate, dihydrate0.0370 4.82 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate0.0230 3.00 F, D, and C Yellow #6 0.0010 0.13 Povidone 29K/32 0.04806.26 DI water q.s. q.s. Phase B Phase A 0.6105 79.60 Sodium laurylsulfate 0.0015 0.20 Sodium starch glycolate 0.0230 3.00 Dibasic Calciumphosphate, dihydrate 0.1245 16.23 Magnesium stearate 0.0075 0.97 TOTAL0.7670 100.00

EXAMPLE 19

The formulation in TABLE XIX exhibited an average disintegration time ofless than 9 minutes in 0.1N HCl and less than 14 minutes in water at37±0.5° C. using the automated disintegration apparatus. TABLE XIXSwallowable Methylcellulose Tablets Formula Ingredient g/tablet (% w/w)Phase A Methocel A4M 0.5000 63.86 Dibasic Calcium phosphate, dihydrate0.0370 4.73 Sodium lauryl sulfate 0.0015 0.19 Sodium starch glycolate0.0230 2.94 F, D, and C Yellow #6 0.0010 0.13 Povidone 29K/32 0.04806.13 DI water q.s. q.s. Phase B Phase A 0.6105 77.97 Sodium laurylsulfate 0.0015 0.19 Sodium starch glycolate 0.0390 4.98 Dibasic Calciumphosphate, dihydrate 0.1245 15.90 Magnesium stearate 0.0075 0.96 TOTAL0.7830 100.00

EXAMPLE 20

Formulations containing a calcium source from the intra andextragranular excipient, dibasic calcium phosphate, dihydrate withextragranular Explotab® are shown in TABLE XX and XXI (Example 21)below.

The formulation in TABLE XX exhibited an average disintegration time ofless than 5 minutes in 0.1N HCl and less than 13 minutes in water at37±0.5° C. using the automated disintegration apparatus. TABLE XXSwallowable Methylcellulose Tablets Formula Ingredient g/tablet (% w/w)Phase A Methocel A4M 0.5000 66.89 Dibasic Calcium phosphate, dihydrate0.0370 4.95 Sodium lauryl sulfate 0.0015 0.20 F, D, and C Yellow #60.0010 0.13 Povidone 29K/32 0.0300 4.01 DI water q.s. q.s. Phase B PhaseA 0.5695 76.19 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate0.0445 5.95 Dibasic Calcium phosphate, dihydrate 0.1245 16.66 Magnesiumstearate 0.0075 1.00 TOTAL 0.7475 100.00

EXAMPLE 21

The formulation in TABLE XXI exhibited an average disintegration time ofless than 7 minutes in 0.1N HCl and less than 9 minutes in water at37±0.5° C. using the conventional disintegration method. TABLE XXISwallowable Methylcellulose Tablets Formula Ingredient g/tablet (% w/w)Phase A Methocel A4M 0.5000 64.52 Dibasic Calcium phosphate, dihydrate0.0370 4.77 Sodium lauryl sulfate 0.0015 0.19 F, D, and C Yellow #60.0010 0.13 Povidone 29K/32 0.0480 6.19 DI water q.s. q.s. Phase B PhaseA 0.5875 75.81 Sodium lauryl sulfate 0.0015 0.19 Sodium starch glycolate0.0235 3.03 Dibasic Calcium phosphate, dihydrate 0.1550 20.00 Magnesiumstearate 0.0075 0.97 TOTAL 0.7750 100.00

EXAMPLE 22

A formulation containing a calcium source from the intra andextragranular xcipient, calcium phosphate, anhydrous with extragranularExplotab® is indicated in TABLE XXII.

The formulation in TABLE XXII exhibited an average disintegration timeof less than 11 minutes in 0.1N HCl and less than 19 minutes in water at37±0.5° C. using the conventional disintegration apparatus. TABLE XXIISwallowable Methylcellulose Tablets Formula Ingredient g/tablet (% w/w)Phase A Methocel A4M 0.5000 66.93 Calcium phosphate, Anhydrous 0.03704.95 Sodium lauryl sulfate 0.0015 0.20 F, D, and C Yellow #6 0.0010 0.13Povidone 29K/32 0.0480 6.43 DI water q.s. q.s. Phase B Phase A 0.587578.65 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0.02603.48 Calcium phosphate, Anhydrous 0.1245 0.67 Magnesium stearate 0.00751.00 TOTAL 0.7470 100.00

EXAMPLE 23

A formulation containing a calcium source from the intra andextragranular excipient, tribasic calcium phosphate WG® withextragranular Explotab® is indicated in TABLE XXIII.

The formulation in TABLE XXIII exhibited an average disintegration timeof less than 13 minutes in 0.1N HCl and less than 24 minutes in water at37±0.5° C. using the conventional disintegration apparatus. TABLE XXIIISwallowable Methylcellulose Tablets Formula Ingredient g/tablet (% w/w)Phase A Methocel A4M 0.5000 66.93 Tribasic Calcium phosphate, WG ®0.0370 4.95 Sodium lauryl sulfate 0.0015 0.20 F, D, and C Yellow #60.0010 0.13 Povidone 29K/32 0.0480 6.43 DI water q.s. q.s. Phase B PhaseA 0.5875 78.65 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate0.0260 3.48 Tribasic Calcium phosphate, WG ® 0.1245 16.67 Magnesiumstearate 0.0075 1.00 TOTAL 0.7470 100.00

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore the Examples herein are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

1-28. (canceled)
 29. A process of preparing a tablet formulation, whichprocess comprising: granulating a methylcellulose; granulating adiluent; blending the granulated methylcellulose and the granulateddiluent to form the intragranulated tablet formulation.
 30. The processof claim 29, wherein the granulated methylcellulose is in an amountbetween 500 mg and 1000 mg.
 31. The process of claim 29, wherein thegranulated methylcellulose is in an amount between 450 mg and 500 mg.32. The process of claim 29, wherein the granulated methylcellulose isin an amount 500 mg.
 33. The process of claim 29, wherein the granulatedmethylcellulose is in an amount between 200 mg and 300 mg.
 34. Theprocess of claim 29, wherein the granulated methylcellulose is in anamount 250 mg.
 35. The process of claim 29, further comprisinggranulating a disintegrating agent.
 36. The process of claim 35, whereinthe disintegrating agent is present in an amount about 3% w/w to about8% w/w.
 37. The process of claim 35, the granulated disintegrating agentis blended with the granulated methylcellulose and the granulateddiluent prior to forming the tablet formulation.
 38. The process ofclaim 29, further comprising granulating a binding agent.
 39. Theprocess of claim 38, wherein the binding agent is present in an amountabout 4% w/w to about 6.5% w/w.
 40. The process of claim 29, furthercomprising granulating a wetting agent.
 41. The process of claim 29,further comprising granulating a lubricating agent.
 42. A process fortreating constipation in a human, which process comprises ingestion bythe human of the tablet formulation of claim
 29. 43. A process fortreating constipation in a human, which process comprises ingestion bythe human of the tablet formulation of claim
 30. 44. A process fortreating constipation in a human, which process comprises ingestion bythe human of the tablet formulation of claim
 31. 45. A process fortreating constipation in a human, which process comprises ingestion bythe human of the tablet formulation of claim 33.